Compositions and methods for weight loss in at risk patient populations

ABSTRACT

The present disclosure relates to compositions, kits, uses, systems and methods related to naltrexone plus bupropion for treating an overweight or obese subject at increased risk of adverse cardiovascular outcomes. Preferably, the subject has had type-two diabetes for a period of less than 6 years or is a current smoker, optionally that does not have type-two diabetes.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.14/635,518, filed Mar. 2, 2015, which is a continuation of U.S.application Ser. No. 14/322,810, filed Jul. 2, 2014, issued as U.S. Pat.No. 8,969,371, which claims the benefit of priorities to U.S. Appl. Nos.61/913,216, filed Dec. 6, 2013; 61/914,938, filed Dec. 11, 2013; and61/984,580, filed Apr. 25, 2014, each of which is hereby incorporated byreferences in its entirety. Any and all priority claims identified inthe Application Data Sheet, or any correction thereto, are herebyincorporated by reference under 37 CFR 1.57.

BACKGROUND

The present disclosure relates to compositions, kits, uses, systems andmethods for treating overweight and obesity using naltrexone andbupropion, or pharmaceutically acceptable salts thereof. In a preferredembodiment the subject is at increased risk of adverse cardiovascularoutcomes, and has type-two diabetes for less than 6 years, or is acurrent smoker, optionally that does not have type-two diabetes.

Obesity has been defined in terms of body mass index (BMI). BMI iscalculated as weight (kg)/[height (m)]². According to the guidelines ofthe U.S. Centers for Disease Control and Prevention (CDC) and the WorldHealth Organization (WHO), for adults over 20 years old, BMI iscategorized as follows: below 18.5 is considered underweight, 18.5-24.9is considered normal, 25.0-29.9 is considered overweight, and 30.0 andabove is considered obese (World Health Organization. Physical status:The use and interpretation of anthropometry. Geneva, Switzerland: WorldHealth Organization 1995. WHO Technical Report Series).

In most of the anti-obesity drug clinical studies, people with type 1 or2 diabetes and other serious medical conditions such as increase risk ofmajor adverse cardiovascular events (MACE) are excluded. Major AdverseCardiovascular Events (“MACEs”) include three primary measurements:nonfatal myocardial infarction (“MI”), nonfatal stroke, andcardiovascular death. These major adverse cardiovascular eventsrepresent serious ischemic events and are widely used endpoints incardiovascular outcome trials.

SUMMARY

Some embodiments disclosed herein are related to methods of treating asubject for overweight or obesity, comprising selecting an overweight orobese subject at increased risk of adverse cardiovascular outcomes thathas had type-two diabetes for a period of less than 6 years; andtreating the subject for overweight or obesity by administering to thesubject a daily dose of 32 mg of sustained release naltrexone, or apharmaceutically acceptable salt thereof and 360 mg bupropion, or apharmaceutically acceptable salt thereof, for a period of at least 12weeks.

Some embodiments disclosed herein are related to methods of treating asubject for overweight or obesity, comprising selecting an overweight orobese subject at increased risk of adverse cardiovascular outcomes thatis a current smoker that does not have type-two diabetes; and treatingthe subject for overweight or obesity by administering to the subject adaily dose of 32 mg of sustained release naltrexone and 360 mgbupropion, or a pharmaceutically acceptable salts thereof, for a periodof at least 12 weeks.

In some embodiments described herein, the subject was administered about8 mg of said sustained release naltrexone or a pharmaceuticallyacceptable salt thereof and about 90 mg of said sustained releasebupropion or a pharmaceutically acceptable salt thereof daily for afirst week of treatment; about 16 mg of said sustained releasenaltrexone or a pharmaceutically acceptable salt thereof and about 180mg of said sustained release bupropion or a pharmaceutically acceptablesalt thereof daily for a second week of treatment; about 24 mg of saidsustained release naltrexone or a pharmaceutically acceptable saltthereof and about 270 mg of said sustained release bupropion or apharmaceutically acceptable salt thereof daily for a third week oftreatment; and about 32 mg of said sustained release naltrexone or apharmaceutically acceptable salt thereof and about 360 mg of saidsustained release bupropion or a pharmaceutically acceptable saltthereof daily for a fourth week of treatment and any subsequent weeks oftreatment.

In some embodiments described herein, the period of treatment is atleast 20 weeks.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphic depiction of the study design of Examples 1 and 2.

FIG. 2 illustrates the time to first major adverse cardiac event (MACE)for patients receiving naltrexone and bupropion (NB32) or placebo.

FIG. 3 illustrates the percent change in body weight from baseline overtime for patients receiving naltrexone and bupropion (NB32) and placebo.

FIG. 4 illustrates the time to cardiovascular death for patientsreceiving naltrexone and bupropion (NB32) or placebo.

FIG. 5 illustrates the time to first myocardial infarction for patientsreceiving naltrexone and bupropion (NB32) or placebo.

FIG. 6 illustrates the time to first stroke for patients receivingnaltrexone and bupropion (NB32) or placebo.

FIG. 7 illustrates the time to all-cause mortality for patientsreceiving naltrexone and bupropion (NB32) or placebo.

FIG. 8 illustrates the mean change in systolic blood pressure frombaseline over time for patients receiving naltrexone and bupropion(NB32) or placebo.

FIG. 9 illustrates the mean change in diastolic blood pressure frombaseline over time for patients receiving naltrexone and bupropion(NB32) or placebo.

DETAILED DESCRIPTION

The combination of naltrexone SR and bupropion SR (Contrave®, NB, orNB32) is being developed by Orexigen Therapeutics, Inc. for treatingoverweight or obese individuals for weight loss and maintenance ofweight loss. To explore the risk of MACE in overweight and obesesubjects treated with naltrexone and bupropion, a double-blind,randomized, placebo-controlled study designed to rule out excesscardiovascular (CV) risk in overweight and obese subjects at increasedrisk of adverse CV outcomes was conducted. This study, described inExample 1, was required by the FDA prior to approval of Contrave becausethe active ingredients in Contrave, particularly bupropion, were knownto increase blood pressure. The FDA was concerned that an increase inblood pressure, while acceptable for the general population, would leadto an unacceptable increase in adverse cardiovascular outcomes in anoverweight/obese patient population. Therefore, patients at higher riskof MACE were treated with Contrave or placebo to determine if Contraveled to an unacceptable increase in adverse cardiovascular outcomes.

Example 2 below summarizes some results of this clinical study.Surprisingly, rather than increasing the occurrence of MACE in this highrisk patient population, the results indicate that treatment withNaltrexone SR/Bupropion SR (Contrave) decreases the occurrence of MACEin overweight and obese subjects with cardiovascular risk factors.Briefly stated, fewer subjects in the Naltrexone SR/Bupropion SRtreatment group experienced a MACE event compared to placebo. Inaddition, a statistically significant effect on MACE was found for twopatient subgroups: patients who have type-2 diabetes for less than 6weeks, and patients who are current smokers. These subgroups saw areduction in the risk of MACE that was greater than the general NBpatient population tested.

In some embodiments, the subject (e.g., patient or patient population)being treated by the methods disclosed herein is overweight or obese andat increased risk of an adverse cardiovascular event. In someembodiments, the MACE is cardiovascular death, nonfatal myocardialinfarction, nonfatal stroke. In some embodiments, the overweight orobese subject at increased risk of adverse CV event or MACE has one ormore characteristics or suffers from one or more of: a history ofcardiovascular disease (CVD); a current confirmed diagnosis or at highlikelihood of CVD; Type 1 diabetes; Type 2 diabetes; dyslipidemia, forexample, elevated triglycerides, elevated LDL, or low HDL; hypertension;past or current smoker; a family history of CVD; a geneticpredisposition of CVD; unstable angina; cardiac arrhythmia; atrialfibrillation; congestive heart failure; and stroke. In a preferredembodiment, the subject is overweight or obese and at increased risk ofa major adverse cardiovascular event, and has Type 2 diabetes mellitus(T2DM) for less than 6 years. In another preferred embodiment, thesubject is overweight or obese and at increased risk of a major adversecardiovascular event, and is a current tobacco smoker. In someembodiments, the current smoker does not have T2DM.

In some embodiments, the overweight or obese subjects that are atincreased risk of adverse CV event or MACE include subjects having oneor more of the following conditions:

(a) cardiovascular disease (CVD) (confirmed diagnosis or at an increasedrisk of CVD) optionally with at least one of the following: a history ofdocumented myocardial infarction>3 months prior to screening oridentification; a history of coronary revascularization (e.g., coronaryartery bypass graft surgery, stent placement, percutaneous transluminalcoronary angioplasty, or laser atherectomy); history of carotid orperipheral revascularization (e.g., carotid endarterectomy, lowerextremity atherosclerotic disease atherectomy, repair of abdominal aortaaneurysm, femoral or popliteal bypass); angina with ischemic changes(resting ECG), ECG changes on a graded exercise test (GXT), or positivecardiac imaging study; ankle brachial index<0.9 (by simple palpation)within prior 2 years; and ≧50% stenosis of a coronary, carotid, or lowerextremity artery within prior 2 years; and/or

(b) Type 2 diabetes mellitus, optionally with at least two of thefollowing: hypertension (controlled with or without pharmacotherapy at<145/95 mm Hg); dyslipidemia requiring pharmacotherapy; documented lowHDL cholesterol (<50 mg/dL in women or <40 mg/dL in men) within prior 12months; and current tobacco smoker.

Reduction or decrease of risk is most easily seen when observing apopulation of treated subjects. Thus, for example, one may observe adecrease in predicted likelihood or risk of MACE in a population bycomparing actual MACE in that treated population to a comparableuntreated population. As used herein, the same conclusion can be drawnfor treatment of an individual or subject falling into an at-risk orenhanced risk category, even if rigid statistical correlations cannot bedemonstrated for that case where n=1. Nevertheless, likelihood of MACEfor an individual subject is considered to be decreased if it isstatistically decreased for any population of subjects to which thatindividual belongs. References herein to reducing or decreasinglikelihood of MACE in a subject should be interpreted to encompassdecreasing for an individual subject and/or decreasing the risk for asubject population, unless the context clearly dictates otherwise.

Some embodiments provided herein include methods in which the subject isbeing treated according to the standard of care with existingmedications, including medications to treat diabetes, dyslipidemia, andhypertension. Thus, the embodiments provided herein includeadministering Naltrexone SR/Bupropion SR to a subject that is at risk ofMACE and that is being treated according to the standard of care with adiabetes, dyslipidemia, or hypertension medication. The embodimentsprovided herein also include administering Naltrexone SR/Bupropion SR toa subject that is taking a diabetes, dyslipidemia, or hypertensionmedication.

In some embodiments, the administration of naltrexone and bupropion iscontinued for a period of, or of about, 1, 2, 3, 4, 6, 8, 10, 12, 16,20, 24, 36, 48, or 52 weeks, or a range defined by any two of thepreceding values.

EXAMPLES

The examples below are non-limiting and are merely representative ofvarious aspects of the invention.

Example 1

A Multicenter, Randomized, Double-Blind, Placebo-Controlled StudyAssessing the Occurrence of Major Adverse Cardiovascular Events (MACE)in Overweight and Obese Subjects With Cardiovascular Risk FactorsReceiving 32 mg Naltrexone SR/360 mg Bupropion SR (“NB” or “NB32”). Thestudy consists of three periods (see FIG. 1):

1) Screening Period (starting at Visit 1, Screen, with informedconsent): up to 2 weeks to verify eligibility prior to the first dose ofstudy medication in the lead-in period.

2) Lead-in Period (starting at Visit 2, Week −2): double-blind, 2-weekperiod during which the subjects receive treatment according to one oftwo sequences: 1 week of active study medication (8 mg naltrexone SR/90mg bupropion SR [NB32]) once a day followed by 1 week of placebo once aday; or 1 week of placebo followed by 1 week of active study medication.Subjects are randomly assigned to NB32 or placebo for the lead-inperiod.

3) Treatment Period (starting at Visit 3, Day 1): double-blind,randomized period during which the subjects who completed the lead-inperiod and satisfied inclusion/exclusion criteria receive active studymedication or placebo. The treatment period starts upon randomization atVisit 3 (Day 1).

a) At Visit 6 (Week 16) there is an evaluation of weight loss and bloodpressure changes relative to baseline observations. The target weightloss is ≧5% with expected minimum weight loss at 16 weeks of ≧2%.Subjects should be discontinued from study medication at Week 16 if:

-   -   they have not lost at least 2% of their body weight or    -   they are experiencing sustained (e.g., at 2 or more visits)        increases in blood pressure (systolic or diastolic) of ≧10 mm        Hg. If the Investigator suspects that an elevated blood pressure        measurement may be spurious, subjects should not be discontinued        until the elevated measurement is confirmed within 4 weeks.

b) All subjects participate in a comprehensive web-based weightmanagement program through completion of study procedures, regardless ofwhether they are taking study medication.

c) Every other month between visits past Visit 7 (Week 26), subjects areasked to answer specific questions pertaining to compliance andhospitalizations (potential MACE or serious adverse events [SAEs]),using an internet- or telephone-based data collection system.

d) All randomized subjects who discontinue study medication earlycomplete the End-of-Treatment Visit procedures and continue toparticipate in the study for the remainder of the trial for collectionof MACE data. Subjects are asked to come to the study site at theirscheduled visits and complete the internet- or telephone-based datacollection every other month between visits past Visit 7 (Week 26) eventhough they are no longer taking study medication.

Subjects must meet all of the following inclusion criteria to beeligible for participation in this study.

-   -   1. ≧50 years of age (women) or ≧45 years of age (men)    -   2. Body mass index (BMI)≧27 kg/m2 and ≦50 kg/m2    -   3. Waist circumference≧88 cm (women) or ≧102 cm (men)    -   4. At increased risk of adverse cardiovascular outcomes:        -   a. Cardiovascular disease (confirmed diagnosis or at high            likelihood of cardiovascular disease) with at least one of            the following:            -   History of documented myocardial infarction>3 months                prior to screening            -   History of coronary revascularization (i.e., coronary                artery bypass graft surgery, stent placement,                percutaneous transluminal coronary angioplasty, or laser                atherectomy)            -   History of carotid or peripheral revascularization                (i.e., carotid endarterectomy, lower extremity                atherosclerotic disease atherectomy, repair of abdominal                aorta aneurysm, femoral or popliteal bypass)            -   Angina with ischemic changes (resting ECG), ECG changes                on a graded exercise test (GXT), or positive cardiac                imaging study            -   Ankle brachial index<0.9 (by simple palpation) within                prior 2 years            -   ≧50% stenosis of a coronary, carotid, or lower extremity                artery within prior 2 years                -   and/or        -   b. Type 2 diabetes mellitus with at least 2 of the            following:            -   Hypertension (controlled with or without pharmacotherapy                at <145/95 mm Hg)            -   Dyslipidemia requiring pharmacotherapy            -   Documented low HDL cholesterol (<50 mg/dL in women or                <40 mg/dL in men) within prior 12 months            -   Current tobacco smoker.

Subjects having the following characteristics are to be excluded:Myocardial infarction within 3 months prior to screening; Anginapectoris Grade III or IV as per the Canadian Cardiovascular Societygrading scheme; Clinical history of cerebrovascular disease (stroke);History of tachyarrhythmia other than sinus tachycardia; Bloodpressure≧145/95 mm Hg, irrespective of treatment with antihypertensiveagents; Unstable weight within 3 months prior to screening (e.g., weightgain or loss of >3%); Planned bariatric surgery, cardiac surgery, orcoronary angioplasty; Severe renal impairment defined by an estimatedGFR<30 mL/min; Clinical history of liver failure or documented ALT orAST greater than 3 times the upper limit of normal (ULN); Knowninfection with HIV or hepatitis; Chronic use or positive screen foropioids; Recent drug or alcohol abuse or dependence (with the exceptionof nicotine dependence) within 6 months prior to screening; History ofseizures (including febrile seizures), cranial trauma, or otherconditions that predispose the subject to seizures; History of mania orcurrent diagnosis of active psychosis, active bulimia or anorexianervosa (binge eating disorder is not exclusionary); At risk for suicideattempts based on the judgment of the Investigator; Acute depressiveillness including new onset of depression or acute exacerbation ofsymptoms (stable subjects on chronic treatment for depression are notexcluded); Any condition with life expectancy anticipated to be lessthan 4 years (e.g., congestive heart failure NYHA Class 3 or 4); Historyof malignancy within the previous 5 years, with exception ofnon-melanoma skin cancer or surgically cured cervical cancer; Currentuse of other bupropion or naltrexone containing products; History ofhypersensitivity or intolerance to naltrexone or bupropion; Use ofmonoamine oxidase inhibitors within 14 days prior to screening; Use ofany investigational drug, device, or procedure within 30 days prior toscreening; Pregnant or breast-feeding women, or currently trying tobecome pregnant, or of child-bearing potential (includingperi-menopausal women who have had a menstrual period within one year)and not willing to practice birth control; Inability to consistentlyaccess broadband internet; Employment by the Sponsor or the study site,or co-habitation with another individual enrolled in the study.

The study medication (NB and placebo) is provided as tablets. Eachactive tablet contains 8 mg naltrexone SR/90 mg bupropion SR (8/90). Alltablets, including placebo, are identical in appearance to maintainblinding. Dose escalation occurs during the first 4 weeks of thetreatment period, as shown in the Table 1 below. Doses can be taken withor without food.

TABLE 1 Treatment Period Lead-in Period Week 1 Week 2 Week 3 Week 4 DoseSchedule Week −2 Week −1 (Days 1-7) (Days 8-14) (Days 15-21) through endof study Total Daily Dose* 8/90 NB 8/90 NB 8/90 NB 16/180 NB 24/270 NB32/360 NB Morning 1 tab NB 1 tab PBO 1 tab NB 1 tab NB 2 tabs NB 2 tabsNB or PBO or NB or PBO or PBO or PBO or PBO Evening — — — 1 tab NB 1 tabNB 2 tabs NB or PBO or PBO or PBO *Doses shown are of naltrexoneSR/bupropion SR (NB); tab = tablet: PBO = placebo.

Example 2

Example 2 summarizes Contrave cardiovascular outcome clinical study(NB-CVOT) results demonstrating that treatment with 32 mg naltrexonesustained-release (SR)/360 mg bupropion SR (NB or NB32) does notincrease or decreases the occurrence of Major Adverse CardiovascularEvents (MACE) in overweight and obese subjects with cardiovascular riskfactors. The general study patient inclusion criteria and protocol aredescribed in the Example 1. The treatment period is ongoing, and theresults reported are interim results.

At Week 16, there was an evaluation of weight loss and blood pressurechanges relative to baseline observations. Subjects were to bediscontinued from study medication at Week 16 if they had not lost atleast 2% of their body weight or they were experiencing consecutive,sustained increases in blood pressure (systolic or diastolic) of ≧10 mmHg.

Study drug is to be administered, double-blind, for 3 to 4 years (2weeks lead-in period and 3 to 4 years treatment period). At the time ofthe interim analysis, mean duration of exposure to study drug was 26.84weeks for the placebo group and 30.47 weeks for the NB group. Totalsubject-years on study medication for the placebo and NB groups were2289 and 2602, respectively.

Overall, 13,192 subjects were screened for eligibility, of which 10,504were enrolled into the lead-in period. A total of 8910 subjects whocompleted the lead-in period were subsequently randomized into thetreatment period and received at least one dose of treatment periodstudy medication (4450 to placebo and 4454 to NB). As of the 6 Nov. 2013data cutoff for the interim analysis, 1201 (placebo) and 1708 (NB)subjects were continuing treatment with study medication. The majorityof the subjects in the ITT Population (95.2%) continued to be followedfor MACE while 4.8% were classified as non-retainable for MACE follow-upbecause they revoked their consent or became lost to follow-up.Importantly, vital status checks using public records were performed forall subjects who were classified as non-retainable for MACE follow-up.Of the 428 subjects who were classified as non-retainable for MACEfollow-up, vital status was obtained for 359 subjects leaving 69subjects (0.8% of the ITT Population) with no vital status (either notobtained or pending) at the time of this interim analysis. The mostcommon reason for discontinuation of study medication during thetreatment period for NB was due to an AE (7.4% placebo, 26.7% NB) andfor placebo was not meeting Week 16 continuation of treatment criteria(40.7% placebo, 14.2% NB). All other reasons for discontinuation ofstudy medication were balanced between treatment groups.

Demographic and Baseline Body Mass Characteristics

Demographic and baseline characteristics for subjects in the ITTPopulation follows. The majority of subjects were female (54.5%), White(83.5%), and not Hispanic or Latino (93.5%). Mean age was 61.0 years.Mean baseline body weight (106.0 kg), BMI (37.3 kg/m2), and waistcircumference (119.5 cm) were consistent with the criteria foroverweight and obese.

The majority of subjects had T2DM (85.2%) with a smaller proportionhaving a history of CV disease (CVD, 32.1%). Treatment assignment wasbalanced within the primary baseline risk groups with an overalldistribution of 67.8%, 14.8%, and 17.3% for T2DM only, CVD only, or T2DMwith CVD, respectively.

Among subjects with T2DM, the median duration of T2DM was 7.7 years with58.9% reporting durations of ≧6 years. Mean baseline HbA1c was 7.4%, and52.7% had an HbA1c≧7%. Antidiabetic medication use at baseline was 78.7%among all subjects in the ITT Population, which reflected primarilymetformin use (63.9%). Subjects with T2DM were not required to have anHbA1c value within a specified range for inclusion in the study andthere were no restrictions on antidiabetic medications.

The incidence of subjects with hypertension at baseline was 92.9%.Antihypertension medication use at baseline was 93.4%, which reflectedprimarily angiotensin-converting enzyme inhibitors (ACEI)/angiotensin IIreceptor blocker (ARB) use (78.0%). Similarly, 91.8% of the subjectsreported dyslipidemia at baseline. Lipid altering medication use atbaseline was 88.4%, which was mostly attributed to statin (HMG-CoAreductase inhibitor) use (80.4%). The incidence of subjects who werecurrent tobacco smokers at screening was 9.2% and comparable betweentreatment groups. The CV related baseline conditions, includinglaboratory values and associated medication use, were comparable betweentreatment groups and indicate that the subjects, while exhibitingincreased CV risk, were also treated for associated comorbiditiesaccording to standard of care.

Demographics and baseline characteristics were balanced betweentreatment groups. There were no unexpected differences in the incidencesand pattern of demographic and baseline characteristics among the CVrisk groups.

Medical History

To qualify for entry into the study, subjects were to be at increasedrisk of CV outcomes by either having CV disease, T2DM, or both asdefined in inclusion criterion 4 of the protocol set forth in Example 1.To be included in the CV disease risk group “CV disease,” subjects wereto have at least one of the following: history of MI>3 months prior toscreening (13.3%); coronary, carotid or peripheral revascularization(25.9%, 0.9%, and 0.7%, respectively); angina with ischemic changes, ECGchanges on a graded exercise test, or positive cardiac imaging study(3.8%); ankle brachial index<0.9 within prior 2 years (0.6%); or ≧50%stenosis of a coronary, carotid, or lower extremity artery within prior2 years (3.6%, 0.7%, and 0.2%, respectively).

To be included in the CV disease risk group “T2DM,” subjects were tohave T2DM (85.2%) with at least two of the following: history ofhypertension (92.9%), dyslipidemia requiring pharmacotherapy (91.8%),documented low HDL within the prior 12 months (29.4%), or was a currentsmoker (9.2%).

CV medical history was balanced between treatment groups. The incidencesand pattern of CV medical history for each CV risk group were expectedfor a population with CV disease, T2DM, or both.

Analyses of Body Weight and Blood Pressure

Overall, mean weight loss was consistently 2% to 3% greater for NB thanplacebo (FIG. 3). The clinically and statistically meaningful weightloss was further demonstrated by the higher proportion of subjectsachieving ≧10% weight loss from baseline to Week 52 with NB (12.3%)compared to placebo (3.3%); odds ratio 4.13 (p<0.0001). The weight lossobserved in this study is consistent with weight loss in subjects withT2DM in previous NB studies, but the absolute and placebo-correctedweight loss is less than observed for the non-diabetic population inprevious studies with NB.

In the NB group, blood pressure values were approximately 0.5 mm Hghigher than placebo at most time points, which peaked at Week 8 with atreatment difference of approximately 1 mm Hg that resolved by Week 16.

Primary MACE Analysis

The incidence of first MACE for the ITT Population is presented in Table2. The total subject-years at risk was similar between the treatmentgroups. The background MACE rate was 1.3% (placebo group), consistentwith the intended target of enrolling subjects with a background MACErate of 1-1.5%.

Fewer subjects treated with NB (35, 0.8%) experienced a primary endpointevent compared to placebo (59, 1.3%); HR (hazard ratio) (95% CI) 0.59(0.39-0.90). The incidence of the individual MACE components of CV deathand nonfatal MI was lower for the NB group than placebo, and theincidence of the MACE component nonfatal stroke was similar betweengroups.

These results clearly meet the pre-specified requirement set forth bythe FDA of excluding a HR of 2.0 (a doubling of the risk). Furthermore,the favorable point estimate and upper bound of the 95% CI of less than1.0 indicate that the risk of MACE with NB is not elevated compared toplacebo. A HR of less than 1.0 indicates that NB reduces the risk ofMACE.

Separation of the primary endpoint results by treatment occurred earlyand was favorable for NB throughout the assessment period (FIG. 2).

TABLE 2 Incidence of First MACE: ITT Population Placebo NB (N = 4450) (N= 4455) MACE, n (%) of Subjects 59 (1.3%) 35 (0.8%) CV Death 16 (0.4%) 5(0.1%) Nonfatal MI 33 (0.7%) 23 (0.5%) Nonfatal Stroke 10 (0.2%) 7(0.2%) Total Subject-years at Risk 4757.7 4769.0 HR (95% CI)¹ 0.59(0.39, 0.90) p-value² <0.0001 Abbreviations: CI = confidence interval;CV = cardiovascular; HR = hazard ratio; MACE = major adversecardiovascular events; MI = myocardial infarction; NB = naltrexone SR 32mg/bupropion SR 360 mg. ¹Based on Cox proportional hazards model withtreatment as a factor. ²p-value for testing the null hypothesis of HR ≧2vs. one-sided alternative.Primary MACE Subgroup Analyses

The primary outcome variable (time to first MACE) was evaluated by thefollowing demographic variables and baseline characteristics: CV riskgroup, age category, sex, race grouping, ethnicity, BMI category,smoking status, HbA1c category, study medication class, duration of T2DMcategory, and renal impairment category. These analyses were conductedto explore potential variation in the treatment effect.

Of the subgroups analyzed, two subgroups showed statisticallysignificant differences in time to first MACE: smoking status andduration of T2DM. The HRs for the incidence of first MACE for thesesubgroups are presented in Table 3 for the ITT Population. The risk forMACE with NB relative to placebo by subgroup was generally similar forthe PP Population.

TABLE 3 Incidence of First MACE by Subgroup: ITT Population SubgroupTreatment N n (%) HR (95% CI)¹ Smoking Status p = 0.0241² No Placebo4036 49 (1.2%) NB 4050 34 (0.8%) 0.69 (0.44, 1.07) Yes Placebo 141 10(2.4%) NB 405  1 (0.2%) 0.10 (0.01, 0.77) Duration of T2DM p = 0.0182²Category <6 years Placebo 1561 18 (1.2%) NB 1494  4 (0.3%) 0.24 (0.08,0.70) ≧6 years Placebo 2166 25 (1.2%) NB 2205 24 (1.1%) 0.93 (0.53,1.64) Abbreviations: CI = confidence interval; NB = naltrexone SR 32mg/bupropion SR 360 mg; T2DM = type 2 diabetes mellitus. ¹Based on Coxproportional hazards model; factors and covariates used to calculate theHR and 95% CI for each subgroup are summarized in the source tables.²Likelihood ratio-test for comparing the model with treatment*subgroupinteraction term and without interaction term.

These results show that subjects that have T2DM less than 6 years have aHR of 0.24, whereas those with T2DM 6 or more years have a HR of 0.93.In comparison, the HR for the entire study population was 0.59. Patientswith T2DM less than 6 years treated with NB have a significantly reducedrisk of MACE compared to those with T2DM 6 or more years. Similarly,subjects that are current smokers have a HR of 0.10, whereas non-smokershave a HR of 0.69. Current smokers treated with NB have a significantlyreduced risk of MACE compared to non-smokers.

Time to Cardiovascular Death

The CV death endpoint includes adjudicated outcomes of sudden cardiacdeath, fatal MI, fatal stroke, and other fatal CV causes. The incidenceof CV death for the ITT Population are presented in Table 4. The HR (95%CI) was 0.26 (0.10, 0.70) and 0.56 (0.16, 1.94) for the ITT and PPPopulations, respectively, indicating that an excess risk of CV deathhas been excluded at the time of the analysis. Sudden cardiac death andother fatal CV causes were the primary contributors to the endpoint.Separation of the CV death endpoint results by treatment for the ITT andPP Populations occurred by Week 20 and was favorable for NB for theremainder of the assessment period (FIG. 4).

TABLE 4 Incidence of Cardiovascular Death ITT Population Placebo NB (N =4450) (N = 4455) CV Death, n (%) of Subjects 19 (0.4%)  5 (0.1%) SuddenCardiac Death 8 (0.2%) 3 (<0.1%) Fatal MI  3 (<0.1%) 1 (<0.1%) FatalStroke  1 (<0.1%) 0 Other Fatal CV Causes 7 (0.2%) 1 (<0.1%) TotalSubject-years at Risk 4782.3 4787.5 HR (95% CI)¹ 0.26 (0.10, 0.70)p-value² <0.0001 Abbreviations: CI = confidence interval; CV =cardiovascular; HR = hazard ratio; MI = myocardial infarction; NB =naltrexone SR 32 mg/bupropion SR 360 mg. ¹Based on Cox proportionalhazards model with treatment as a factor. ²p-value for testing the nullhypothesis of HR ≧2 vs. one-sided alternative.Time to First Myocardial Infarction

The MI endpoint includes adjudicated outcomes of fatal and nonfatal MI.The incidence of first MI for the ITT Population is presented in Table5. The HR (95% CI) was 0.70 (0.42, 1.19) and 0.83 (0.40, 1.71) for theITT and PP Populations, respectively, indicating that an excess risk ofMI has been excluded at the time of the analysis. Throughout the study,the risk of MI with NB was either favorable or similar to placebo forthe ITT and PP Populations (FIG. 5).

TABLE 5 Incidence of First Myocardial Infarction ITT Population PlaceboNB (N = 4450) (N = 4455) MI, n (%) of Subjects 34 (0.8%) 24 (0.5%)Nonfatal MI 33 (0.7%) 23 (0.5%) Fatal MI  1 (<0.1%) 1 (<0.1%) TotalSubject-years at Risk 4763.1 4773.2 HR (95% CI)¹ 0.70 (0.42, 1.19)p-value² <0.0001 Abbreviations: CI = confidence interval; HR = hazardratio; MI = myocardial infarction; NB = naltrexone SR 32 mg/bupropion SR360 mg. ¹Based on Cox proportional hazards model with treatment as afactor. ²p-value for testing the null hypothesis of HR ≧2 vs. one-sidedalternative.Time to First Stroke

The stroke endpoint includes adjudicated outcomes of fatal and nonfatalstroke. The incidence of first stroke for the ITT Population ispresented in Table 6. The HR (95% CI) was 0.63 (0.25, 1.64) for the ITTPopulation, indicating that an excess risk of stroke has been excludedat the time of the analysis for this population.

Separation of the stroke endpoint results by treatment for the ITTPopulation occurred after Week 20 and was favorable for NB for theremainder of the assessment period (FIG. 6); the proportion of subjectswith stroke in the PP Population was generally similar between treatmentgroups throughout the study.

TABLE 6 Incidence of First Stroke ITT Population Placebo NB (N = 4450)(N = 4455) Stroke, n (%) of Subjects 11 (0.2%) 7 (0.2%) Nonfatal Stroke10 (0.2%) 7 (0.2%) Fatal Stroke  1 (<0.1%) 0 Total Subject-years at Risk4777.0 4783.3 HR (95% CI)¹ 0.63 (0.25, 1.64) p-value² 0.0088Abbreviations: CI = confidence interval; HR = hazard ratio; NB =naltrexone SR 32 mg/bupropion SR 360 mg. ¹Based on Cox proportionalhazards model with treatment as a factor. ²p-value for testing the nullhypothesis of HR ≧2 vs. one-sided alternative.All-Cause Mortality Endpoint and Other Cardiovascular Endpoints

An overview of the all-cause mortality endpoint and other CV endpointmeasures for the ITT Population is presented in Table 7. The HR (95% CI)for all-cause mortality had a point estimate favoring NB (0.45 [0.22,0.96]). As expected given the population and study design, CV death wasthe primary contributor to the all-cause mortality endpoint. Separationof the all-cause mortality endpoint results by treatment for the ITTPopulation occurred after Week 16 and was favorable for NB for theremainder of the assessment period (FIG. 7). More subjects treated withNB experienced an endpoint event of HUSA (29, 0.7%) compared to placebo(23, 0.5%); HR (95% CI) 1.26 (0.73, 2.18). Separation of HUSA endpointresults by treatment for the ITT Population occurred early and wasfavorable for placebo. Importantly, this observation was not associatedwith an increase in coronary revascularization events (HR [95% CI] of1.00 [0.71, 1.41]). An endpoint event of coronary revascularizationprocedures was experienced by 65 (1.5%) subjects in each treatmentgroup. Throughout the study, the risk of coronary revascularizationevents with NB was similar to placebo for the ITT Population.

The HR (95% CI) for first five-point expanded MACE had a point estimatefavoring NB (0.87 [0.65, 1.15]). Five-point expanded MACE includesadjudicated outcomes of CV death, nonfatal MI, nonfatal stroke, nonfatalHUSA, and coronary revascularization procedure. The incidence of firstcoronary revascularization procedure, the only term not included forfour-point expanded MACE, was similar for both treatment groups (0.7%each). The all-cause mortality endpoint and other CV endpoint measureswere also evaluated for the ITT Population by CV risk group, agecategory, sex, race grouping, ethnicity, and BMI category.

TABLE 7 Incidence of All-Cause Mortality Endpoint and OtherCardiovascular Endpoints ITT Population Placebo NB (N = 4450) (N = 4455)All-Cause Mortality, n (%) of 22 (0.5%) 10 (0.2%) Subjects CV Death 19(0.4%) 5 (0.1%) Non-CV Death  3 (<0.1%) 5 (0.1%) Total Subject-years atRisk 4782.3 4787.5 HR (95% CI)¹ 0.45 (0.22, 0.96) p-value² <0.0001Abbreviations: CI = confidence interval; CV = cardiovascular; HR =hazard ratio; NB = naltrexone SR 32 mg/bupropion SR 360 mg. ¹Based onCox proportional hazards model with treatment as a factor. ²p-value fortesting the null hypothesis of HR ≧2 vs. one-sided alternative.Change in Systolic Blood Pressure

The mean change in systolic blood pressure from baseline by visit forthe ITT (with LOCF) Population is presented in FIG. 8. Note that only44.8% of subjects had completed the Week 52 visit prior to the interimanalysis cut-off date. Thus, the last observation taken at the time ofthe cut-off date was carried forward to Week 52 for subjects receivingmedication who had not yet reached Week 52. Blood pressure changes wereslightly more favorable with placebo than NB at each time point. In theplacebo group, mean systolic blood pressure decreased below baseline atWeek 2, then steadily increased through Week 52. In the NB group,systolic blood pressure values were approximately 0.5 mm Hg higher thanplacebo at most time points, which peaked at Week 8 with a treatmentdifference of approximately 1 mm Hg that resolved by Week 16.

Subjects who did not meet the continuation of treatment criteria due tosustained increases in blood pressure (or insufficient weight loss) werediscontinued from treatment, which is reflected in a sharp decrease inthe systolic blood pressure after Week 16 for both treatment groups forthe PP Population compared to the ITT Population (with LOCF).Additionally, all subjects in the NB group were on treatment at eachtime point per the PP Population definition and under thesympathomimetic effects of bupropion, which contributed to the magnitudeof the treatment difference after Week 16 compared to the ITT Population(with LOCF).

Change in Diastolic Blood Pressure

The mean change in diastolic blood pressure from baseline by visit forthe ITT (with LOCF) Population is presented in FIG. 9. Note that only44.8% of subjects had completed the Week 52 visit prior to the interimanalysis cut-off date. Thus, the last observation taken at the time ofthe cut-off date was carried forward to Week 52 for subjects receivingmedication who had not yet reached Week 52. Blood pressure changes weremore favorable with placebo than NB at each time point. In the placebogroup, mean diastolic blood pressure was within 1 mm Hg from baseline ateach time point through Week 52. In the NB group, diastolic bloodpressure values were approximately 0.5 mm Hg higher than placebo at mosttime points, which peaked at Week 8 with a treatment difference ofapproximately 1 mm Hg that resolved by Week 16.

Subjects who did not meet the continuation of treatment criteria due tosustained increases in blood pressure (or insufficient weight loss) werediscontinued from treatment, which is reflected in a sharp decrease inthe diastolic blood pressure after Week 16 for both treatment groups forthe PP Population compared to the ITT Population (with LOCF).Additionally, all subjects in the NB group were on treatment at eachtime point per the PP Population definition and under thesympathomimetic effects of bupropion, which contributed to the magnitudeof the treatment difference after Week 16 compared to the ITT Population(with LOCF).

Overall, the small relative increases in diastolic blood pressure withNB treatment relative to placebo in NB-CVOT are consistent with thatobserved in the Phase 3 program.

Conclusions

In conclusion, the favorable point estimate for the hazard ratio (HR)and upper bound of the 95% CI of less than 1.0 at the time of thisinterim analysis indicate that the risk of MACE in overweight and obesesubjects treated with NB is not increased compared to those receivingplacebo. The point estimate for primary MACE observed in this study (HR[95% CI]: 0.59 [0.39, 0.90]) suggests that the treatment with NB reducesthe risk of MACE, rather than increasing it as anticipated by the FDA.Of note, these favorable results were observed in a population welltreated according to standard of care with medications to treatdiabetes, dyslipidemia, and hypertension. Despite the small relativeincreases in blood pressure with NB treatment, which were also observedin earlier trials, the results of the MACE endpoints at the time of theinterim analysis clearly suggests no harm related to the mildsympathomimetic action of NB.

While the patient population receiving NB had a reduced HR for MACE, twoNB patient subpopulations demonstrated a statistically significanteffect on the risk of MACE: smoking status and duration of T2DM. Currentsmokers (HR [95% CI]: 0.10 [0.01, 0.77]) and patients with T2DM lessthan 6 years (HR [95% CI]:0.24 [0.08, 0.70]) showed a greater reductionin the risk of MACE compared to non-smokers (HR [95% CI]: 0.69 [0.44,1.07]) and patients with T2DM 6 or more years (HR [95% CI]: 0.93 (0.53,1.64]). Based on these results, overweight or obese patients atincreased risk of adverse cardiovascular events who are current smokersor have T2DM less than 6 years will benefit from treatment with NB bysignificantly reducing their risk of MACE compared to the generalpopulation of overweight or obese patients at increased risk of adversecardiovascular events.

What is claimed is:
 1. A method of treating a subject for overweight or obesity, comprising: selecting an overweight or obese subject at increased risk of adverse cardiovascular outcomes that has had type-two diabetes for a period of less than 6 years; and treating the subject for overweight or obesity by administering to the subject a daily dose of 32 mg of sustained release naltrexone, or a pharmaceutically acceptable salt thereof and 360 mg bupropion, or a pharmaceutically acceptable salt thereof, for a period of at least 12 weeks.
 2. A method of treating a subject for overweight or obesity, comprising: selecting an overweight or obese subject at increased risk of adverse cardiovascular outcomes that is a current smoker that does not have type-two diabetes; and treating the subject for overweight or obesity by administering to the subject a daily dose of 32 mg of sustained release naltrexone and 360 mg bupropion, or a pharmaceutically acceptable salts thereof, for a period of at least 12 weeks.
 3. The method of claim 1, wherein the subject was administered: about 8 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 90 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a first week of treatment; about 16 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 180 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a second week of treatment; about 24 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 270 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a third week of treatment; and about 32 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 360 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a fourth week of treatment and any subsequent weeks of treatment.
 4. The method of claim 1, wherein the period of treatment is at least 20 weeks.
 5. The method of claim 2, wherein the subject was administered: about 8 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 90 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a first week of treatment; about 16 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 180 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a second week of treatment; about 24 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 270 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a third week of treatment; and about 32 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 360 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a fourth week of treatment and any subsequent weeks of treatment.
 6. The method of claim 2, wherein the period of treatment is at least 20 weeks.
 7. The method of claim 1, wherein the adverse cardiovascular outcome is selected from the group consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.
 8. The method of claim 1, wherein the adverse cardiovascular outcome is cardiovascular death.
 9. The method of claim 2, wherein the adverse cardiovascular outcome is selected from the group consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.
 10. The method of claim 2, wherein adverse cardiovascular outcome is cardiovascular death.
 11. A method of treating a subject for overweight or obesity, comprising: administering to said subject a daily dose of 32 mg of sustained release naltrexone, or a pharmaceutically acceptable salt thereof and 360 mg bupropion, or a pharmaceutically acceptable salt thereof, for a period of at least 12 weeks, wherein said subject is at increased risk of adverse cardiovascular outcomes and has had type-two diabetes for a period of less than 6 years.
 12. The method of claim 11, wherein the subject was administered: about 8 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 90 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a first week of treatment; about 16 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 180 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a second week of treatment; about 24 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 270 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a third week of treatment; and about 32 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 360 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a fourth week of treatment and any subsequent weeks of treatment.
 13. The method of claim 11, wherein the period of treatment is at least 20 weeks.
 14. The method of claim 11, wherein the adverse cardiovascular outcome is selected from the group consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.
 15. The method of claim 11, wherein the adverse cardiovascular outcome is cardiovascular death.
 16. A method of treating a subject for overweight or obesity, comprising: administering to the subject a daily dose of 32 mg of sustained release naltrexone and 360 mg bupropion, or a pharmaceutically acceptable salts thereof, for a period of at least 12 weeks, wherein said subject is at increased risk of adverse cardiovascular outcomes and is a current smoker that does not have type-two diabetes.
 17. The method of claim 16, wherein the subject was administered: about 8 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 90 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a first week of treatment; about 16 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 180 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a second week of treatment; about 24 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 270 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a third week of treatment; and about 32 mg of said sustained release naltrexone or a pharmaceutically acceptable salt thereof and about 360 mg of said sustained release bupropion or a pharmaceutically acceptable salt thereof daily for a fourth week of treatment and any subsequent weeks of treatment.
 18. The method of claim 16, wherein the period of treatment is at least 20 weeks.
 19. The method of claim 16, wherein the adverse cardiovascular outcome is selected from the group consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.
 20. The method of claim 16, wherein the adverse cardiovascular outcome is cardiovascular death. 